Process for the synthesis of derivatives of 2,3-dihydro-1,4-dioxino- [2,3-f] quinoline

ABSTRACT

Methods of preparing compounds of Formula Iare provided.

This application claims priority from co-pending provisional applicationSer. No. 60/291,547, filed on May 17, 2001, the entire disclosure ofwhich is hereby incorporated by reference.

FIELD OF THE INVENTION

This invention relates to a novel process of producing derivatives of2,3-dihydro-1,4-dioxino [2,3-f]quinoline in a highly convergent andefficient manner, as well as intermediates thereof. Compounds of thepresent invention are SSRI/5-HT_(1A) antagonists useful for thetreatment of diseases which are caused or affected by disorders of theserotonin-affected neurological systems such as depression, includingchildhood depression, obsessive compulsive disorders, panic disorder,generalized anxiety disorder, social anxiety disorders, sexualdysfunction, eating disorders such as bulimia, obesity, addictivedisorders caused by ethanol or cocaine abuse and dysthymia as describedin copending application Ser. No. 60/275,564 filed Mar. 14, 2001.

SUMMARY OF THE INVENTION

In accordance with the present invention is provided methods of makingcompounds of Formula I:

wherein

R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms;

R², R³, R⁴, and R⁶ are, independently, hydrogen, hydroxy, halo, cyano,carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxyof 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which eachalkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms,or alkanesulfonamido of 1 to 6 carbon atoms

R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms;

A dotted line represents an optional double bond;

A and D are selected from carbon, substituted by R¹, and nitrogen,provided that at least one of A and D is nitrogen;

E and G are carbon, substituted by R¹; and

Z is N or CR⁶;

or pharmaceutically acceptable salts thereof, comprising the steps of:

a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;

with a halogenating reagent to afford a compound of the formula:

wherein X is Br, Cl, or I;

b) dealkylating the compound of Formula 3 in an acid to afford acompound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with asulfonating reagent to afford a compound of the formula:

wherein R′″ is an aryl-, or alkyl-sulfonate and

g) coupling the compound of Formula 8 with the appropriateazaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.

In alternative embodiments of the present invention the hydroxy moietyof compounds of Formula 7 may be activated to halide to afford acompound of the formula:

wherein X is I, Br, or Cl and

the compound of Formula 10 may be coupled with the appropriateazaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.

In other embodiments of the present invention are provided methods ofmaking compounds of Formula I

comprising the steps of:

a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;

with a halogenating reagent in a solvent to afford a compound of theformula:

wherein X is Br, Cl, or I;

b) dealkylating the compound of Formula 3 in an acid to afford acompound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with asulfonating reagent to afford a compound of the formula:

wherein R′″ is an aryl- or alkyl-sulfonate; and

g) coupling the compound of Formula 8 with the appropriateazaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.

In alternative embodiments of the present invention the hydroxy moietyof compounds of Formula 7 may be activated to halide to afford acompound of the formula:

wherein X is I, Br, or Cl and

the compound of Formula 10 may be coupled with the appropriateazaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.

In some embodiments of the present invention is provided a method ofmaking a compound of Formula Ia

comprising the steps:

a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;

with a halogenating reagent to afford a compound of the formula:

wherein X is Br, Cl, or I;

b) dealkylating the compound of Formula 3a in an acid to afford acompound of the formula:

c) alkylating the compound of Formula 4a with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl; to afford a compound of theformula:

d) cyclizing the compound of Formula 5a with palladium or coppercatalyst to afford a compound of the formula:

e) debenzylating the compound of Formula 6a to afford a compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7a with asulfonating reagent to afford a compound of the formula:

wherein R′″ is an aryl- or alkyl-sulfonate; and

g) coupling the compound of Formula 8a with 3-tetrahydropyridinyl-indolein the presence of base to provide a compound of Formula Ia.

Alternatively, the hydroxy moiety of compounds of Formula 7a may beactivated to halide to afford a compound of Formula 10a

wherein X is I, Br, or Cl and

the compound of Formula 10a may be coupled with3-tetrahydropyridinyl-indole in the presence of base to provide acompound of Formula Ia.

In accordance with other aspects of the invention is provided a methodof preparing compounds of Formula 5:

wherein A, D, E, G, X and R″ are as defined for Formula I and R″ isbenzyl or substituted benzyl, comprising alkylating the compound ofFormula 4

with R″ protected glycidyl ethers

wherein R″ is benzyl or substituted benzyl. In some embodiments of theinvention A is nitrogen, D is carbon substituted with methyl, and E andG are unsubstituted carbon.

Further in accordance with the present invention is provided a method ofpreparing compound of Formula 6

where A, D, E and G are as defined for Formula I, and R″ is benzyl orsubstituted benzyl, comprising the step of cyclizing a compound ofFormula 5

with palladium or copper catalyst. In some embodiments of the inventionA is nitrogen, D is carbon substituted with methyl, and E and G areunsubstituted carbon.

Further in accordance with the invention is provided a method ofpreparing compound of Formula 8

wherein A, D, E and G are defined as for Formula I and R′″ is an aryl-or alkyl-sulfonate; comprising activating the hydroxy moiety of thecompound of Formula 7

with a sulfonating reagent. In some embodiments of the invention A isnitrogen, D is carbon substituted with methyl, and E and G areunsubstituted carbon.

Further in accordance with the invention is provided a method ofpreparing compound of Formula 10

wherein A, D, E and G are as defined for Formula I, and X is I, Cl orBr, comprising activating compound of Formula 7

to halide with halophosphorous such as phosphorous triiodide,phosphorous tribromide or phosphorous pentachloride, or with thionylhalide or any standard halogenating reagent.

Further in accordance with the present invention is provided a method ofpreparing compound of Formula 7

wherein A, D, E and G are as defined Formula I, comprising debenzylatinga compound of Formula 6

where R″ is benzyl or substituted benzyl.

In some embodiments of the invention A is nitrogen, D is carbonsubstituted with methyl and E and G are unsubstituted carbon.

In some embodiments of the invention compound of Formula 2

is halogenated with a halogenating agent such as N-halosuccinimidewherein halo means bromo-, chloro-, or iodo- in a suitable solvent suchas acetonitrile.

In other embodiments of the invention compound of Formula 3

is demethylated with a Lewis acid in a solvent or a strong protic acid.Preferred Lewis acids include, but are not limited to, boron tribromide,boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyliodine. The preferred solvent is methylene chloride. Strong protic acidsinclude, but are not limited to, HBr and HCl.

Compound of Formula 4

may be alkylated with R″ protected glycidyl ethers

wherein R″ is benzyl or substituted benzyl in a polar solvent. Forinstance R″ may be benzyl, 4-bromobenzyl, 4-chlorobenzyl,3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxyphenyl.

Exemplary polar solvents useful in alkylation of compounds of Formula 4include dimethylsulfoxide (DMSO), dimethylforamide (DMF),dimethylacetamide (DMA).

Alkylation may be performed in the presence of a base such as, but notlimited to, triethylamine, sodium carbonate, or potassium carbonate.

Compound of Formula 5 can be cyclized using palladium catalysts such as,but not limited to, tris(dibenzylideneacetone)dipalladium,tetrakis(triphenyl-phosphine)palladium, or palladium acetate withphosphine ligands including but not limited to (±)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (BINAP) and separateenantiomers thereof; (±) 2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl(Tol-BINAP) and separate enantiomers thereof;1-1′-bis(diphenylphosphino)ferrocene; 1,3-bis(diphenylphosphino)propane;and 1,2 bis(diphenylphosphino)ethane in the presence of bases such assodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH),potassium carbonate, sodium carbonate, titanium carbonate, cesiumcarbonate, potassium t-butoxide or potassium phosphate tribasic insuitable solvent such as toluene.

Alternatively, compound of Formula 5 can be cyclized with coppercatalyst such as copper iodide in the presence of bases such as NaH,LiH, KH in a suitable solvent such as toluene.

Debenzylation of compound of Formula 6 can be carried out with Lewisacids such as boron tribromide, boron trichloride, aluminum trichloride,ferric chloride, trimethylsilyl iodine in a suitable solvent such asmethylene chloride.

Debenzylation of compound of Formula 6 may also be carried out withstrong protic acids such as HBr and HCl, or alternatively, underreductive cleavage conditions using Pd catalyst and hydrogen transferreagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammoniumformate.

The hydroxy moiety of compound of Formula 7 is activated with asulfonating reagent such as aryl or alkyl sulfonyl chloride or alkyl oraryl sulfonic anhydride in the presence of a base such as triethylamineor pyridine in suitable solvents such as methylene chloride,tetrahydrofuran (THF), or toluene. Alkyl, as used herein preferablyrefers to alkyl of 1-6 carbon atom. Aryl, as used herein preferablyrefers to phenyl. Preferred sulfonating reagents include, but are notlimited to p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3-or 4-nitrobenzenesulfonyl chloride, 2- or 4-bromo-benzenesulfonylchloride, or trifiluoromethylsulfonic anhydride.

Alternatively the hydroxy moiety of compound of Formula 7 is activatedas halogen, such as 1, Br or Cl with reagent such as I₃P, Br₃P Cl₅P orSOCl₂ to provide compound of Formula 10.

Compound of Formula 8 or 10 are coupled with azaheterocycles of Formula9 including 3-tetrahydropyridinyl-indole in the presence of bases suchas sodium carbonate, potassium carbonate, or Hünig's base in suitablepolar solvents such as THF, dioxane, DMSO, DMF, or DMA to affordcompound of Formula I.

Still further in accordance with the present invention are providednovel intermediates of the formula

wherein:

R₇ is hydroxy, alkoxy of 1-6 carbon atoms, or alkoxy of the formula

wherein R₉ is hydroxy, benzyl ether, substituted benzyl ethers such as4-bromo-benzyl ether, 4-chlorobenzyl ether, 3,4-dimethoxybenzyl ether,2- or 4-nitrobenzyl ether, or

4-methoxyphenyl; and

R₈ is halogen or hydrogen; and salts thereof.

A is nitrogen and D is carbon in preferred intermediates of Formula II.

Also in accordance with the present invention are novel intermediates ofthe formula

wherein:

R₁₀ is hydroxy, halide or aryl or alkyl sulfonates; and salts thereof.

A is nitrogen and D is carbon in preferred intermediates of Formula III.

Certain compounds of the present invention contain one asymmetric carbonatom, giving rise to enantiomeric forms of the compounds. It is to beunderstood that the invention encompasses the enantiomers thereofincluding racemic mixtures.

It is known that compounds possessing a basic nitrogen can be complexedwith many different acids (both protic and non-protic). The inventionalso includes acceptable salt forms formed from the addition reactionwith either inorganic or organic acids. Inorganic acids such ashydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI),sulfuric acid, phosphoric acid, nitric acid are useful as well asorganic acids such as acetic acid, propionic acid, citric acid, maleicacid, malic acid, tartaric acid, phthalic acid, succinic acid,methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid,camphorsulfonic acid, benzenesulfonic acid are useful.

“Halo” as used herein, such as in the term “halosuccinimide” refers tohalogen and preferably bromo-, chloro-, or iodo-.

DETAILED DESCRIPTION OF INVENTION

Thus, in accordance with the present invention is provided a process forpreparing in high yield enantiomerically pure compounds of Formula I aswell as intermediate thereof.

The process of the present invention can be illustrated by the followingreaction scheme (Scheme I), wherein A, D, E, G, R′, R″, R′″, and X areas stated above. The reagents and the solvents for the individual stepare given for illustrative purposes only and may be replaced by reagentsand solvents known to those skilled in the art.

This process is characterized by high yields and purity of the productsand technical convenience. The synthesis of compound I comprises stepsthat begin with halogenation of 2 with halogenating reagents such asN-halosuccinimide in acetonitrile to give 3. Deprotecting 3 with Lewisacids such as boron tribromide, boron trichloride, aluminum trichloride,ferric chloride, or trimethylsilyl iodide in a suitable solvent such asmethylene chloride, or with strong protic acids such as HBr and HCl togive the salt of 4. Free base 4 is very water soluble and neutralizationis achieved from an Amberlyst A-21 resin slurry in polar solvents suchas ethanol or methanol.

Alkylation of 4, either as the free base or as the salt, with benzyl orsubstituted benzyl protected glycidyl ethers in suitable polar solventssuch as dimethylsulfoxide (DMSO), dimethylformamide (DMF), or dimethylacetamide (DMA) in the presence of bases such as sodium carbonate,potassium carbonate, or triethylamine gives 5.

Compound 5 is cyclized using palladium catalysts such astris-(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate with ligandsfrom the group consisting of (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) and separateenantiomers thereof; (±) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl(Tol-BINAP) and separate enantiomers thereof;1-1′-bis(diphenyl-phosphino) ferrocene;1,3-bis(diphenyl-phosphino)propane; and1,2-bis(diphenyl-phosphino)ethane in the presence of bases such as NaH,LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate,cesium carbonate, potassium t-butoxide or potassium phosphate tribasicin suitable solvent such as toluene; or alternatively, with coppercatalyst such as copper iodide in the presence of bases such NaH, LiH,KH in a suitable solvent such as toluene to afford quinoline 6. Similardioxanes may also be prepared using the above reagents.

Deprotection of quinoline 6 with Lewis acids such as boron tribromide,boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyliodide in a suitable solvent such as methylene chloride, or with strongprotic acids such as HBr and HCl or under reductive cleavage conditionsusing Pd catalyst and hydrogen transfer reagents such as hydrogen,cyclohexene, methyl cyclohexene, or ammonium formate to gives 7. Thehydroxyl moiety of 7 can be activated with a sulfonating reagent such asan aryl or alkyl sulfonyl chloride or aryl or alkyl sulfonic anhydridesuch as p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or4-nitro-benzenesulfonyl chloride, 2- or 4-bromobenzenesulfonyl chloride,or trifluoromethylsulfonic anhydride in the presence of bases such astriethylamine or pyridine in suitable solvents such as methylenechloride, THF, or toluene to afford 8. The final coupling of 8 withazaheterocycle 9, prepared by reaction of indole with the hydrochloridesalt of 4-piperidone, in the presence of bases such as Hunig's base,potassium carbonate, or sodium carbonate in polar solvents such as THF,dioxane, DMSO, DMF, or DMA affords final compound I.

The following examples illustrate the process of the present inventionbut are not meant to be limiting thereof.

EXAMPLE 1 Preparation of 5-Bromo-6-Methoxy-2-Methylquinoline

A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) inacetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wiseaddition of N-bromosuccinimide (200 g, 1.12 mol) over a period of 30 minwhile maintaining the same temperature. The resulted brown slurry waswarmed to ambient temperature and stirred for an additional 6 h. Thereaction was then quenched by a 10% NaHSO₃ solution (211 mL). Thereaction mixture was concentrated to a volume of 600 mL then slowlypoured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at roomtemperature for 1 h then filtered, washed with water (2×1 L) and driedin a vacuum oven to give 253 g (98.6%) of the title compound as a brownsolid.

R_(f)=0.39 (3:7) EtOAc:heptane;

¹H NMR (DMSO) δ8.30 (d, J=6.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H), 7.70 (d,J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H);

¹³C NMR (DMSO) δ156.9, 153.1, 143.2, 133.6, 129.3, 126.0, 123.6, 117.0,106.1, 56.9, 24.3;

IR (KBr): υ_(max) 3435, 3197, 2943, 2843, 1699, 1613, 1599, 1495, 1342,1305, 1267, 1131, 1067, 968, 870, 811, 629 cm⁻¹;

Analysis for C₁₁H₁₀NOBr: Calculated: C, 52.40; H, 3.97; N, 5.56. Found:C, 52.13; H, 3.94; N, 5.61.

EXAMPLE 2 Preparation of the Hydrobromide Salt of5-Bromo-2-Methyl-6-Quinolinol

A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48%HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in 1 h togive a brown and thick slurry. The slurry was stirred at 0-5° C. for 1 hthen filtered, washed with EtOAc (2×50 mL) and dried in a vacuum oven togive 34.9 g (92%) of the title compound as a brown solid.

¹H NMR (DMSO) δ8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.56 (d,J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H);

¹³C NMR (DMSO) δ155.7, 152.0, 142.8, 133.3, 128.9, 126.4, 123.3, 121.2,103.3, 24.1.

EXAMPLE 3 Preparation of 5-Bromo-2-Methyl-6-Quinolinol

A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washedwith MeOH then dried in oven) in MeOH (35 mL) was stirred at roomtemperature for 3 h. The mixture was then filtered and concentrated invacuo to give 2.5 g (100%) of a yellow solid.

R_(f)=0.36 (1:1) EtOAc:heptane;

¹H NMR (DMSO) δ8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t,J=9.1 Hz, 2H), 2.66 (s, 3H);

EXAMPLE 4 Preparation of(2S)-1-(Benzyloxy)-3-[(5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanol

A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol),(R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g,172 mmol) in DMA (200 mL) was heated in a 95-98° C. oil bath for 2 days.The solution was cooled and poured into water (300 mL) while stirring.The tan precipitate formed was filtered, washed with water (100 mL) anddried in a vacuum oven to give 37 g (73%) of the title compound as a tansolid.

R_(f)=0.35 (EtOAc);

¹H NMR (DMSO) δ8.31 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.72 (d,J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.25-7.36 (m, 5H), 5.28 (d, J=5.1Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m, 2H), 4.08-4.15 (m, 1H), 3.61-3.73(m, 2H), 2.66 (s, 3H);

¹³C NMR (DMSO) δ157.0, 152.7, 143.4, 138.4, 133.7, 129.2, 128.1, 127.4,127.3, 126.0, 123.6, 118.4, 106.8, 72.4, 71.3, 71.2, 68.1, 24.3;

IR (KBr): υ_(max) 3391, 3188, 2938, 2875, 1597, 1497, 1268, 1061, 817,697 cm⁻¹;

Specific rotation=+6.2° (c=1, CH₃OH);

Analysis for C₂₀H₂₀BrNO₃: Calculated: C, 59.66; H, 4.97; N, 3.48. Found:C, 59.43; H, 4.97; N, 3.55.

EXAMPLE 5 Preparation of(2S)-1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanolfrom 5-Bromo-2-Methyl-6-Quinolinol Salt

In a rapidly stirred mixture of K₂CO₃ (597 g, 4.32 mol)) in DMF (3 L),HBr salt of 5-bromo-2-methyl-6-quinolinol (551 g, 1.73 mol) was addedover 30-60 min at rt. After cooling the mixture to room temperature,(R)-benzyl glycidyl ether (353 g, 2.07 mol) was added rapidly. Thereaction mixture was then heated to 70° C. for from 50-70 h beforecooling to 20-23° C. Water (6.05 L) was added over a period of 30-120min. The reaction mixture was filtered and the filtered cake was washedwith additional water (1 L). The solid was then stirred in water (3 L)for 30-40 min and filtered. The filtered cake was washed with water (1L). The solid obtained was then dried in a vacuum oven (5-0.5 mm Hg) at65° C. over 8-16 h to give 662 g of the title compound. The crudeproduct was then recrystallized in EtOH (2.5 L) to give 487 g (70%) ofthe title compound as an off-white solid.

EXAMPLE 6 Palladium Catalyzed Preparation of(2S)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

A solution of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (10g, 24.9 mmol), potassium phosphate tribasic (11.4 g, 50 mmol), Pd(OAc)₂(280 mg, 1.25 mmol) and racemic BINAP (1.55 g, 2.49 mmol) in toluene (50mL) was heated in a 100-102° C. oil bath for 3 d. The solution wascooled to room temperature then EtOAc (50 mL) and water (50 mL) wereadded. The reaction mixture was filtered through a bed of celite. Thetwo layers were separated. The aqueous layer was extracted with EtOAc(30 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to give 8 g (100%) of the crude product as abrown syrup. The crude product can be carried through the debenzylationstep before purification. A sample of the crude mixture was purified onSiO₂, eluted with (3:1) hexane:EtOAc gave the title compound as a yellowoil which solidified upon standing.

R_(f)=0.5 (EtOAc);

¹H NMR (DMSO) δ8.24 (d, J=8.6 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.27-7.38(m, 7H);

¹³C NMR (DMSO) δ156.4, 143.3, 138.1, 137.9, 135.2, 128.4, 128.2, 127.2,127.4, 121.4, 121.0, 120.9, 118.1, 72.5, 72.4, 68.2, 65.1, 24.5;

IR (KBr): υ_(max) 3413, 3280, 3028, 2917, 2886, 3798, 1628, 1601, 1572,1485, 1453, 1374, 1257, 1100, 1056, 982 cm⁻¹;

Specific Rotation=+7.9° (c=1.2, CHCl₃);

Analysis for C₂₀H₁₉NO₃: Calculated: C, 74.68; H, 5.91; N, 4.36. Found:C, 74.48; H, 6.03; N, 4.14.

EXAMPLE 7 Copper Catalyzed Preparation of(2S)-2[(Benzyloxy)methyl-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

To a mixture of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene(2 L), NaH (10.9 g, 0.45 mol) was added in portions at 30-35° C. over 20min. The reaction mixture was kept at 35° C. for 30 min then heated to110° C. slowly. After 30 min, the reaction was cooled to 600C,additional NaH (10.9 g, 0.45 mol) was added. This was warmed to 110° C.for an additional 2 hours then cooled to rt before dropwise addition ofwater (200 mL). After stirring for −15 min, the mixture was filteredthrough a bed of celite then washed with toluene (3×50 mL) and water (50mL). The two layers were separated. The organic layer was extracted withwater (100 mL), NH₄OH (100 mL), 25% NaCl (100 mL) and concentrated invacuo to give 387.6 g of the crude product as a brown syrup. The crudeproduct was carried through to the debenzylation step beforepurification (see example 10).

EXAMPLE 8 Lewis Acid Catalyzed Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

To a solution of(2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.74 g, 2.3 mmol) in CH₂Cl₂ (16 mL) being cooled in anice-bath, FeCl₃ (1.9 g, 12 mmol) was added. After 1 h, the ice-bath wasremoved and the reaction mixture was stirred for another 17 h. CHCl₃ (30mL) and 1 N NaOH (50 mL) were added to result in a suspension which wasthen filtered. The filtered solid was washed with CH₃OH (50 mL). Thecombined organic layers were concentrated in vacuo. Purification onSiO₂, eluted with (10:1) CHCl₃:iPrOH gave 0.45 g (84%) of the titlecompound as an off-white solid.

R_(f)=0.34 (EtOAc);

¹H NMR (DMSO) δ8.29 (d, J=6.6 Hz, 1H), 7.42 (d, J=6.6 Hz, 1H), 7.30-7.37(m, 2H), 5.13 (t, J=4.3 Hz, 1H), 4.43-4.46 (m, 1H), 4.31-4.33 (m, 1H),4.09-4.14 (m, 1H), 3.70-3.78 (m, 2H), 2.60 (s, 3H);

¹³C NMR (DMSO) δ156.7, 143.6, 138.4, 135.9, 129.0, 121.7, 121.4, 121.1,118.5, 78.4, 74.4, 65.6, 60.3, 24.9;

IR (KBr): υ_(max) 3200, 2917, 2849, 1628, 1601, 1488, 1374, 1341, 1265,1107, 1079, 1050, 809 cm⁻¹;

GC/MS 231, 212, 200, 186, 175, 168, 156, 145, 129, 117, 110, 102, 89,76,64, 57, 50, 39, 31.

EXAMPLE 9 Palladium Catalyzed Preparation of[(2S)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

To a solution of(2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene(0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated toreflux under N₂ for 18 h then cooled and filtered. The catalyst wasrinsed with methanol and the filtrate was concentrated in vacuo toafford 0.113 g (98%) of the title alcohol as an off-white solid.

¹H NMR (CD₃OD) δ8.46 (m, 1H), 7.47 (m, 1H), 7.38−7.31 (m, 2H), 4.40 (m,1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H).

EXAMPLE 10 Protic Acid Catalyzed Preparation of[(2S)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

A mixture of crude (2S)-2[(benzyloxy)methyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoline product mixture (57.6 g, 0.179 mol) from example 7 intoluene (300 mL) was mixed with 20% HCl (436 g, 3.59 mol) and heated at80° C. After 30 min, the reaction mixture was cooled to roomtemperature. The two layers were separated. A 30% NH₄OH solution (400mL) was added to the aqueous layer at 10-20° C. to pH 10. This wasstirred for 30 min, the solid was filtered, washed with water andrecrystallized from CH₃OH (200 mL) to give 25.7 g (61.9%) of the titlealcohol as an off-white solid.

EXAMPLE 11 Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Bromobenzenesulfonate

A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol(4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylaminopyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) intoluene (40 mL) was stirred at 60° C. for 6 h. The reaction mixture wascooled to room temperature then water (20 mL) was added. After 30 min,the two layers were separated. The organic layer was extracted with 8%NaHCO₃ (20 mL) and H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The solid obtained was dissolved in isopropylalcohol (50 mL) and toluene (10 mL) at 80° C., cooled to roomtemperature over 1 h then filtered, washed with (5:1) IPA: toluene (2×5mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the titlecompound as an off-white solid.

¹³C NMR (CDCl₃) δ157.9, 144.3, 138.1, 134.7, 132.9, 129.7, 129.6, 129.0,122.4, 121.7, 121.3, 118.8, 70.7, 67.6, 64.5, 25.4

EXAMPLE 12 Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Methylbenzenesulfonate

A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol(0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) andtriethylamine (0.65 mL, 4.7 mmol) in CH₂Cl₂ (8 mL) was stirred at roomtemperature for 18 h. CHCl₃ (30 mL) and H₂O (30 mL) were added. The twolayers were separated. The aqueous layer was extracted with CHCl₃ (20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification on SiO₂, eluting with (1:1)hexane:EtOAc gave 0.19 g (88%) of the title compound as a brown syrup.

R_(f)=0.43 (CHCl₃:iPrOH);

mp: 115-117° C.;

¹H NMR (CDCl₃) δ8.12 (d, J=8.6 Hz, 1H), 7.76 (m, 2H), 7.51 (d, J=9 Hz,1H), 7.20-7.60 (m, 4H), 4.5-4.6 (m, 1H), 4.2-4.4 (m, 3H), 4.1-4.2 (m,1H), 2.70 (s, 3H);

¹³C NMR (DMSO) δ156.9, 145.4, 143.6, 137.9, 134.7, 132.2, 130.4, 128.7,128.0, 121.8, 121.6, 121.3, 121.3, 118.3, 70.9, 68.6, 64.1, 60.1, 24.9,21.4, 21.1, 14.4; GC/MS 385, 213, 186, 174, 145, 130, 117, 102, 91, 77,65, 52, 41, 30;

IR (KBr): υ_(max) 3625, 3374, 2924, 1732, 1628, 1601, 1573, 1485, 1359,1251, 1177, 1096, 1049, 941, 818, 664, 554 cm⁻¹.

EXAMPLE 13 Formation of 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-Indole

A mixture of indole (1.01 g, 8.59 mmol), 4-piperidone monohydratehydrochloride (1.99 g, 12.9 mmol) and KOH (1.74 g, 31 mmol) in CH₃OH (9mL) was heated to reflux for 21 h. After cooling the reaction mixture toroom temperature, H₂O (14 mL) was added. The suspension was filtered,the solid was washed with (1:1) MeOH:H₂O (20 mL) and air-dried to give1.49 g (87%) of the title compound as an off-white solid.

¹H NMR (DMSO) δ11.1 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.3-7.5 (m, 2H),7.0-7.2 (m, 2H), 6.16 (m, 2H), 3.3-3.5 (m, 2H), 2.9 (t, J=5.7 Hz, 2H),2.38 (m, 2H);

¹³C NMR (DMSO) δ137.0, 130.1, 124.7, 122.3, 121.1, 120.1, 119.9, 119.1,116.7, 111.7, 45.0, 43.0, 40.1, 39.9, 39.7, 39.5, 39.3, 39.3, 39.1,38.9, 28.3.

EXAMPLE 14 Preparation of(2S)-2-[4-(1H-Indol-3-yl)-3,6-Dihydro-2H-Pyridin-1-ylmethyl]-8-Methyl-2,3-Dihydro-1,4-Dioxino[2,3-f]Quinoline

A solution of[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-methylbenzenesulfonate (0.192 g, 0.499 mmol),3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.119 g, 0.601 mmol) andK₂CO₃ (0.104 g, 0.753 mmol) in (1:1) THF:DMF (1.4 mL) was heated to80-83° C. for 10 h. After this time, H₂O (3 mL) was added and thesuspension was filtered. The filtered solid was washed with CH₃OH (2×3mL), Et₂O (2×5 mL) and air-dried to give 0.148 g (72%) of the titlecompound as a tan solid.

R_(f)=0.18 (EtOAc);

¹H NMR (DMSO) δ11.1 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 7.82 (d, J-7.8 Hz,1H), 7.25-7.50 (m, 4H), 6.9-7.2 (m, 2H), 6.14 (s, 1H), 4.4-4.7 (m, 2H),4.0-4.2 (m, 1H), 2.7-3.0 (m, 4H), 2.4-2.7 (m, 8H);

¹³C NMR (DMSO) δ156.8, 146.8, 143.6, 138.4, 137.3, 135.6, 130.0, 128.9,125.0, 123.1, 121.8, 121.6, 121.5, 121.2, 120.4, 119.6, 118.5, 117.9,116.2, 112.1, 72.1, 66.8, 58.0, 53.8, 51.1, 28.9, 24.9;

IR (KBr): υ_(max) 3410, 3240, 3059, 2848, 1601, 1484, 1403, 1352,1255,1096, 982, 818, 745 cm⁻¹.

EXAMPLE 15 Preparation of(2S)-2-[4-(1H-Indol-3-yl)-3,6-Dihydro-2H-Pyridin-1-ylmethyl]-8-Methyl-2,3-Dihydro-1,4-Dioxino[2,3-f]Quinoline

A solution of[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzenesulfonate (2.0 g, 4.44 mmol),3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.01 g, 5.09 mmol) anddiisopropylethyl amine (0.86 g, 6.65 mmol) in DMSO (10 mL) was heated to80-83° C. After 10 h, the reaction mixture was cooled to 65-70° C.before CH₃OH (3 mL) was added. The resulted suspension was cooled toroom temperature, filtered, washed with CH₃OH and dried in a vacuum ovento give 1.3 g (71%) of the title compound as a yellow solid.

EXAMPLE 16 Preparation of(2R)-1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanolfrom 5-Bromo-2-Methyl-6-Quinolinol

A solution of 5-bromo-2-methyl-6-quinolinol (2.50 g, 10.5 mmol),(S)-benzyl glycidyl ether (2.1 g, 12.8 mmol) and triethylamine (0.54 g,5.3 mmol) in DMA (25 mL) was heated in a 80-83° C. oil bath for 2 d. Thesolution was cooled and poured into water (20 mL) while stirring. Thetan precipitate formed was filtered, washed with water (10 mL) and driedin a vacuum oven to give 3.0 g (71%) of the title compound as a tansolid.

EXAMPLE 17 Preparation of1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanol from5-Bromo-2-Methyl-6-Quinolinol Salt

A solution of 5-bromo-2-methyl-6-quinolinol (1.0 g, 4.2 mmol), benzylglycidyl ether (0.83 g, 5.1 mmol) and triethylamine (0.21 g, 2.1 mmol)in DMA (15 mL) was heated in a 90-95° C. oil bath for 18 h. The solutionwas cooled and poured into water (30 mL) and Et₂O (100 mL). The twolayers were separated. The aqueous layer was extracted with Et₂O (2×50mL). The organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give 1.3 g (74%) of the titled compound as atan solid.

EXAMPLE 18 Palladium Catalyzed Preparation of(2R)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

A mixture of(2R)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(2.9 g, 7.2 mmol) and NaH (0.48 g, 12 mmol) in toluene (15 mL) wasstirred in a 50-52° C. oil bath for 40 min. This was then canulated intoa mixture of Pd(OAc)₂ (82 mg, 0.36 mmol) and racemic BINAP (451 mg,0.724 mmol) in toluene (10 mL) in a 50-52° C. oil bath. The resultedreaction mixture was degassed 3 times with Ar before heated to 100-102°C. in an oil bath. After 20 h, the reaction mixture was cooled to roomtemperature then sat'd NH₄Cl (60 mL) and EtOAc (60 mL) were added. Thiswas stirred for 20 min before filtering through a bed of celite. The twolayers were separated. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. Purification on SiO₂, eluting with (3:1)hexane:EtOAc gave 1.4 g (56%) of the title compound as a brown oil.

EXAMPLE 19 Palladium Catalyzed Preparation of2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

A mixture of1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (1.1 g,2.7 mmol) and NaH (175 mg, 4.4 mmol) in toluene (10 mL) was stirred in a50-52° C. oil bath for 30 min. This was then canulated into a mixture ofPd(OAc)₂ (31 mg, 0.14 mmol) and (R)-Tol-BINAP (186 mg, 0.274 mmol) intoluene (10 mL) in a 50-52° C. oil bath. The resulted reaction mixturewas degassed 3 times with Ar before heated to 100-102° C. in an oilbath. After 18 h, the reaction mixture was cooled to room temperaturethen sat'd NH₄Cl (30 mL) and EtOAc (30 mL) were added. This was filteredthrough a bed of celite. The two layers were separated. The aqueouslayer was extracted with EtOAc (2×20 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo.Purification on SiO₂, eluting with (3:1) hexane:EtOAc gave 0.52 g (58%)of the title compound as a yellow oil.

EXAMPLE 20 Preparation of[8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Methylbenzenesulfonate

A solution of[8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol (0.13 g,0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine (0.65mL, 4.7 mmol) in CH₂Cl₂ (8 mL) was stirred at room temperature for 18 h.CHCl₃ (30 mL) and H₂O (30 mL) were added. The two layers were separated.The aqueous layer was extracted with CHCl₃ (20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo.Purification on SiO₂, eluting with (1:1) hexane:EtOAc gave 0.19 g (88%)of the title compound as a brown syrup.

R_(f)=0.44 (EtOAc);

¹H NMR (CDCl₃) δ8.12 (d, J=8.6 Hz, 1H), 7.76 (m, 2H), 7.51 (d, J=9 Hz,1H), 7.20-7.60 (m, 4H), 4.5-4.6 (m, 1H), 4.2-4.4 (m, 3H), 4.1-4.2 (m,1H), 2.70 (s, 3H), 2.39 (s, 3H).

EXAMPLE 21 Lewis Acid Catalyzed Preparation of[8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

To a solution of 2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.30 g, 0.94 mmol) in CH₂Cl₂ (8 mL) being cooled in anice-bath, FeCl₃ (0.77 g, 4.7 mmol) was added. After 1 h, the ice-bathwas removed and the reaction mixture was stirred for another 4 h. CH₂Cl₂(30 mL) and 1N NaOH (25 mL) were added to result in a suspension whichwas then filtered. The filtered solid was washed with CH₃OH (50 mL). Thecombined organic layers were concentrated in vacuo. Purification onSiO₂, eluted with (10:1) CHCl₃:iPrOH gave 0.15 g (68%) of the titlecompound as an off-white solid.

What is claimed is:
 1. A method of making compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of: a) halogenating a compound of the formula:

wherein R¹ is alkyl of 1-6 carbon atoms; with a halogenating reagent toafford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with asulfonating reagent to afford a compound of the formula:

wherein R′″ is an aryl- or alkyl- sulfonate; and g) coupling thecompound of Formula 8 with the appropriate azaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I


2. A method of making compounds of formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon substituted by R¹ and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl, or alkyl alcohol of 1 to 6carbon atoms to afford compound of the formula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 withalkyl- or aryl- sulfonyl chloride or with alkyl or aryl sulfonicanhydride in the presence of a base to afford a compound of the formula:

wherein R′″ is an alkyl- or aryl-sulfonate; and g) coupling the compoundof Formula 8 with the appropriate azaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.
 3. A methodof making compounds of formula Ia:

comprising the steps: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protect glycidyl ethers

wherein R″ is benzyl or substituted benzyl; to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with alkylor aryl sulfonyl chloride with alkyl or aryl sulfonic anhydride in thepresence of a base to afford a compound of the formula:

wherein R′″ is a alkyl- or aryl-sulfonate; and g) coupling the compoundof Formula 8 with 3-tetrahydropyridinyl-indole in the presence of baseto provide a compound of Formula Ia.
 4. The method of claim 1 whereinthe compound of Formula 2 is treated with N-halosuccinimide inacetonitrile.
 5. The method of claim 1 wherein the halogenation reactionis quenched with a 10% NaHSO3 solution and the product precipitated withNaOH.
 6. The method of claim 1 wherein the compound of Formula 3 isdealkylated with a Lewis acid.
 7. The method of claim 1 wherein thecompound of Formula 3 is dealkylated with a protic acid.
 8. The methodof claim 7 wherein the protic acid is HBr.
 9. The method of claim 8wherein the compound of Formula 2 is heated to reflux in HBr for fromabout 6 to about 7 hours.
 10. The method of claim 1 wherein the compoundof Formula 4 is alkylated with benzyl- or substituted benzyl-glycidylether in a polar solvent.
 11. The method of claim 1 wherein the compoundof Formula 4 is alkylated with benzyl glycidyl ether, 4-bromobenzylglycidyl ether, 4-chlorobenzyl glycidyl ether, 3,4-dimethoxybenzylglycidyl ether, 2- or 4-nitrobenzyl glycidyl ether, or 4-methoxy-phenylglycidyl ether.
 12. The method of claim 10 wherein the polar solvent isdimethylsulfoxide, dimethyl-formamide, or dimethylacetamide.
 13. Themethod of claim 10 wherein the base is triethylamine, sodium carbonate,or potassium carbonate.
 14. The method of claim 1 wherein the compoundof Formula 5 is cyclized using palladium catalyst in the presence ofphosphine ligand and base.
 15. The method of claim 14 wherein thepalladium catalyst is tris(dibenzylidene-acetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate withphosphine ligands selected from the group consisting of (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and separate enantiomersthereof; (±) 2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl and separateenantiomers thereof; 1-1′-bis(diphenylphosphino)ferrocene;1,3-bis(diphenyl-phosphino)propane; and1,2-bis(diphenylphosphino)ethane.
 16. The method of claim 14 wherein thebase is sodium hydride, lithium hydride, potassium hydride, potassiumcarbonate, sodium carbonate, titanium carbonate, cesium carbonate,potassium t-butoxide or potassium phosphate tribasic.
 17. The method ofclaim 1 wherein the compound of Formula 5 is cyclized using coppercatalyst in the presence of base.
 18. The method of claim 17 wherein thecopper catalyst is copper iodide.
 19. The method of claim 17 wherein thebase is sodium hydride, lithium hydride or potassium hydride.
 20. Themethod of claim 1 wherein the compound of Formula 6 is debenzylated withLewis acid, strong protic acid or under reductive cleavage conditions.21. The method of claim 20 wherein the Lewis acid is boron tribromide,boron trichloride, aluminum trichloride, ferric chloride ortrimethylsilyl iodine.
 22. The method of claim 20 wherein the proticacid is hydrobromic acid or hydrochloric acid.
 23. The method of claim 1wherein a) the compound of Formula 5 is cyclized using copper catalystin the presence of Nail to provide compound of Formula 6, and b)compound of Formula 6 is debenzylated with HCl to provide compound ofFormula
 7. 24. The method of claim 20 wherein reductive cleavage isperformed using palladium catalyst and hydrogen transfer reagents. 25.The method of claim 24 wherein the palladium catalyst is Pd/C.
 26. Themethod of claim 24 wherein the transfer reagent is cyclohexene,methylcyclohexene, ammonium formate or hydrogen.
 27. The method of claim24 wherein the palladium catalyst is Pd/C and the transfer reagent iscyclohexene.
 28. The method of claim 1 wherein the compound of Formula 7is activated with a sulfonating reagent or with an aryl or alkylsulfonic anhydride in the presence of a base.
 29. The method of claim 28wherein the compound of Formula 7 is activated with p-toluenesulfonylchloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonylchloride, 2- or 4-bromobenzenesulfonyl chloride ortrifluoromethylsulfonic anhydride.
 30. The method of claim 28 whereinthe compound of Formula 7 is activated with4-bromobenzenesulfonylchloride.
 31. The method of claim 28 wherein thebase is triethylamine or pyridine in methylene chloride,tetrahydrofuran, or toluene.
 32. The method of claim 1 wherein thecompound of Formula 8 is coupled with an azaheterocycle of Formula 9 inthe presence of a base.
 33. The method of claim 32 wherein the base issodium carbonate, potassium carbonate, or Hünig's base.
 34. A method ofmaking compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 to ahalide to afford a compound of the formula:

wherein X is I, Br or Cl and g) coupling the compound of Formula 10 withthe appropriate azaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.
 35. Themethod of claim 34 wherein the compound of Formula 7 is activated with ahalogenating reagent.
 36. The method of claim 34 wherein the compound ofFormula 7 is activated as a halide with phosphorous triiodide,phosphorous tribromide, phosphorous pentachioride or thionyl chloride.37. A method of making compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof comprising thesteps of: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 to ahalide to afford a compound of the formula:

wherein X is I, Br or Cl; and g) coupling the compound of Formula 10with the appropriate azaheterocycle of Formula 9

in the presence of base to provide a compound of Formula I.
 38. A methodof making a compound of Formula Ia:

comprising the steps: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3a inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4a with R″ protected glycidylethers

wherein R″ is benzyl or substituted benzyl; to afford compound of theformula:

d) cyclizing the compound of Formula 5a with palladium or coppercatalyst to afford a compound of the formula:

e) debenzylating the compound of Formula 6a to afford the compound ofthe formula:

f) activating the hydroxy moiety of the compound of Formula 7a to ahalide to afford a compound of the formula:

wherein X is I, Br or Cl; and g) coupling the compound of Formula 10awith 3-tetrahydropyridinyl-indole in the presence of base to provide acompound of Formula Ia.